Tacrolimus administration to a patient with cyclosporine-induced encephalopathy after allogeneic bone marrow transplantation

A 25-year-old woman with severe aplastic anemia received allogeneic bone marrow transplantation from an HLA-identical sibling. Pretransplant conditioning comprised 3.6 Gy of total body irradiation and 200 mg/kg cyclophosphamide. Cyclosporine (CSP) and methotrexate were administered to prevent graft-versus-host disease (GVHD). The patient complained of severe headache soon after CSP administration on day-1. On day 3, convulsion developed and she lost consciousness for 15 min. CT and MRI demonstrated low density areas and high signals, respectively, in the frontal and parietooccipital lobes and splenium of the corpus callosum, suggesting brain edema probably induced by CSP. After immediate withdrawal of CSP, glycerol and prednisolone were instituted, and the patient's condition improved. Thereafter, she developed grade II acute GVHD. This was treated with tacrolimus, which produced no adverse effects including central nervous system (CNS) toxicity. This case illustrates that careful management of CNS disorders induced by CSP can be important in patients undergoing allogeneic bone marrow transplantation.     

Cross‐sectional analysis of germline BRCA1 and BRCA2 mutations in Japanese patients suspected to have hereditary breast/ovarian cancer

The prevalence of BRCA1/2 germline mutations in Japanese patients suspected to have hereditary breast/ovarian cancer was examined by a multi‐institutional study, aiming at the clinical application of total sequencing analysis and validation of assay sensitivity in Japanese people using a cross‐sectional approach based on genetic factors estimated from personal and family histories. One hundred and thirty‐five subjects were referred to the genetic counseling clinics and enrolled in the study. Full sequencing analysis of the BRCA1/2 gene showed 28 types of deleterious mutations in 36 subjects (26.7%), including 13 types of BRCA1 mutations in 17 subjects (12.6%) and 15 types of BRCA2 mutations in 19 subjects (14.1%). Subjects were classified into five groups and 22 subgroups according to their personal and family history of breast and/or ovarian cancer, and the prevalence of deleterious mutations was compared with previously reported data in non‐Ashkenazi individuals. Statistical analysis using the Mantel‐Haenszel test for groups I through IV revealed that the prevalence of Japanese subjects was significantly higher than that of non‐Ashkenazi individuals (P = 0.005, odds ratio 1.87, 95% confidence interval 1.22–2.88). Family history of the probands suffering from breast cancer indicated risk factors for the presence of deleterious mutations of BRCA1/2 as follows: (1) families with breast cancer before age 40 within second degree relatives (P = 0.0265, odds ratio 2.833, 95% confidence interval 1.165–7.136) and (2) families with bilateral breast cancer and/or ovarian cancer within second degree relatives (P = 0.0151, odds ratio 2.88, 95% confidence interval 1.25–6.64). (Cancer Sci 2008; 99: 1967–1976)     

Cardiac Beriberi (Shoshin Beriberi) Caused by Excessive Intake of Isotonic Drink

A 21 month old female had voluntarily ingested 0.5–1.51 of isotonic sports drink daily from 10 months of age. She developed hyponatremia and beriberi heart disease, which resulted in metabolic acidosis and cardiogenic shock (shoshin beriberi). Mechanical ventilation was applied for pulmonary edema. Right heart failure was improved after administering vitamin Bi. However, 5 days after the shock, hypoxemia and diffuse radiographic infiltrates progressed, and a diagnosis of adult respiratory distress syndrome (ARDS) was made. After the occurrence of an air leak, the patient died of respiratory failure. The cardiogenic shock and pulmonary edema due to cardiac beriberi may have triggered the ARDS.     

Diagnostic usefulness of diffusion-weighted magnetic resonance imaging in influenza-associated acute encephalopathy or encephalitis

A magnetic resonance imaging (MRI) study was performed for a 20-month-old girl with an influenza type A infection who presented acute encephalopathy. Conventional MRI performed 8 days after the onset of encephalopathy, including T1-weighted, T2-weighted, and fluid-attenuated inversion recovery imaging, revealed only vague lesions in the right frontal, temporal, and parietal lobes. In contrast, diffusion-weighted imaging (DWI) then demonstrated the lesions much more intensively. On the 26th day, the lesions previously observed on DWI had become less discernible. The hyperintensity observed on DWI might reflect cytotoxic edema. Thus, DWI may be useful for evaluation of acute influenzal encephalopathy/encephalitis.     

Identification and use of biomarkers in Gaucher disease and other lysosomal storage diseases

The value of biomarkers in the clinical management of lysosomal storage diseases is best illustrated by the present use of plasma chitotriosidase levels in the diagnosis and monitoring of Gaucher disease. The enzyme chitotriosidase is specifically produced and secreted by the pathological storage macrophages (Gaucher cells). Plasma chitotriosidase levels are elevated on average 1000-fold in symptomatic patients with Gaucher disease and reflect the body burden on storage cells. Changes in plasma chitotriosidase reflect changes in clinical symptoms. Monitoring of plasma chitotriosidase levels is nowadays commonly used in decision making regarding initiation and optimization of costly therapeutic interventions (enzyme replacement therapy or substrate reduction therapy). A novel substrate has been developed that further facilitates the measurement of chitotriosidase in plasma samples. Moreover, an alternative Gaucher-cell marker, CCL18, has been very recently identified and can also be employed to monitor the disease, particularly in those patients lacking chitotriosidase due to a genetic mutation. There is a need for comparable surrogate markers for other lysosomal storage diseases and the search for such molecules is an area of intense investigation.
Conclusion: The use of biomarkers can provide valuable insight into the molecular pathogenesis of LSDs, such as Gaucher disease and Fabry disease.     

Renal tubular acidosis associated with zonisamide therapy

PURPOSE: We sought to report a previously undescribed adverse effect, renal tubular acidosis associated with zonisamide (ZNS) therapy. METHODS: Ammonium chloride, bicarbonate, and furosemide loading tests were performed in an epileptic patient with metabolic acidosis and episodic hypokalemia who was treated with ZNS. RESULTS: Distal renal tubular acidosis was diagnosed. On reexamination 7 weeks after ZNS had been replaced with phenytoin, the renal tubular acidosis disappeared. CONCLUSIONS: This case indicates, for the first time, that ZNS might be a potential cause of renal tubular acidosis. Blood gases and serum electrolytes should be measured in patients undergoing ZNS therapy.     

Antibodies to tumor necrosis factor alpha prevent increases in cell replication in liver due to the potent peroxisome proliferator, WY- 14,643

Several structurally dissimilar hypolipidemic drugs, plasticizers and halogenated hydrocarbons induce peroxisomes in hepatocytes, and cause hepatocellular adenoma and carcinoma in rats and mice. The mechanism by which these agents act is unknown, although recent studies have suggested a link between increased cell proliferation and hepatic cancer caused by peroxisome proliferators. Here, we demonstrate that neutralizing antibodies to tumor necrosis factor alpha (TNF alpha) block increases in protein kinase C and cell proliferation due to [4- chloro-6-(2,3-xylidino)-2-pyrimidinylthio]acetic acid (WY-14,643), a hypolipidemic drug and potent peroxisome proliferator that causes tumors. WY-14,643 moderately elevated the level of TNF alpha mRNA in the liver. TNF alpha was detected immunohistochemically exclusively in Kupffer cells. These results demonstrate that WY-14,643 acts as an indirect mitogen on hepatocytes via TNF alpha. We propose that the Kupffer cell, a major source of TNF alpha in the liver, is involved in the mechanism of the mitogenic effect of WY-14,643.      

Evaluation of attempted prevention of unexpected infant death in very high-risk infants by planned health care

Three hundred and ninety-six babies born in Sheffield between 1982 and 1990 identified as being at "very high risk" of unexpected infant death by means of a scoring system, received an intensive programme of health care including a case discussion between a paediatrician, the GP and the health visitor held in the family doctor's surgery, weekly visits from the health visitor and informal hospital admission. Significantly fewer sudden unexpected infant deaths occurred in this group than were expected by logistic regression anlysis or occurred in the best available control group with comparable scores ( p = 0.024). Problems in evaluation include identification of an adequate control population, ethical difficulties in introducing a controlled study when the programme is already perceived as effective, and the calculation of "expected death rates". The results of this study indicate that very energetic programmes of intervention may prevent some deaths in vulnerable infants.     

Serum profiles of insulin-like growth factors and their binding proteins in adults with growth hormone receptor deficiency treated with insulin like growth factor I

Six adult patients with growth hormone receptor deficiency (GHRD) (2 men, 4 women) with an identical defect in the growth hormone receptor (GHR) gene, were treated with recombinant human insulin-like growth factor I (IGF-I), 40 μgikg S.C. twice daily, for 7 days. Serum concentrations of IGF peptide and IGF binding protein-3 (IGFBP-3) were measured by specific radioimmunoassays; serum IGFBPs were also measured by Western ligand blotting. The size distribution of both IGF-I and IGF-II was measured in serum following size-exclusion fast-performance liquid chromatography. IGF-I treatment resulted in a normalization of serum IGF-I levels on days 1–7 of treatment and a decrease in serum IGF-II levels. The fall in IGF-II levels and the simultaneous rise in IGF-I levels, however, resulted in an unchanged total serum IGF level. The low IGFBP-3 values did not significantly change during treatment, whereas there was a slight increase in IGFBP-2 levels. Preliminary analysis of size-fractionated sera suggested an increase in IGF-I levels in the 40 and 150 kDa regions at the expense of IGF-II levels. The results suggest that despite the failure of IGF-I treatment to increase IGFBPs significantly, serum IGFBP concentrations were sufficient to maintain normal levels of IGF-I. 0 Laron syndrome, growth hormone receptor deficiency, insulin-like growth factors, insulin-like growth factor binding protein